Therapeutic Efficacy and Safety of Amitriptyline in Patients with Cystic Fibrosis

Abstract

Amitriptyline, a blocker of acid sphingomyelinase and acid ceramidase, significantly reduces Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) mice with concurrent increase of survival. Our aim was to establish whether amitriptyline is safe and effective in the treatment of CF patients. In a randomised, double-blinded, placebo-controlled, cross-over pilot study, 4 adult CF patients received 37.5 mg of amitriptyline or placebo twice daily for 14 days. Subsequently in a phase II study 19 adult CF patients were randomly allocated to three treatment groups receiving amitriptyline once daily for 28 days at doses of 25 mg (n=7), 50 mg (n=8), or 75 mg (n=8) or placebo (n=13). The primary outcome was the difference of forced expiratory volume in 1 sec (FEV₁) at day 14 between amitriptyline and placebo. Primary endpoint measures improved significantly in three of four patients in the pilot study after amitriptyline treatment vs placebo (relative FEV₁: 14.7±5%; p = 0.006) and in the 25 mg treatment group of the phase II study (relative FEV₁: 4.0±7%; p = 0.048). Amitriptyline was well tolerated in both studies and 96% of the patients completed the studies. Amitriptyline as a novel therapeutic option in patients with CF is safe and seems to be efficacious.

Therapy of CF-Patients with Amitriptyline and Placebo - a Randomised, Double-Blind, Placebo-Controlled Phase IIb Multicenter, Cohort-Study

“…Based on the results of our previous studies [15], we used the difference of relative FEV 1 predicted between cases and controls after treatment of 28 days as primary endpoint.…”

“…We have previously assessed the therapeutic efficacy and safety of amitriptyline in a pilot study involving 4 CF patients treated with amitriptyline or placebo demonstrating a significant increase in lung function after 2 weeks of treatment with amitriptyline. We subsequently performed a phase IIa study for safety, proof-of-mechanism and dose-finding study involving 19 CF patients [15]. This study revealed that amitriptyline is safe in CF patients, since only mild adverse effects were observed.…”

“…This study revealed that amitriptyline is safe in CF patients, since only mild adverse effects were observed. Moreover, the per protocol (PP) analysis of this study demonstrated a 5% increase of the forced expiratory volume in one second (FEV 1 ) after treatment with amitriptyline compared to the placebo group suggesting an improvement of lung functions by amitriptyline [15]. Although it is difficult to exactly determine the complex physiology and pathophysiology of the lung in CF patients, medical associations (European Medicines Agency, Food and Drug Administration, USA) suggested to use the FEV 1 , i.e.…”

Glucosylceramide Critically Contributes to the Host Defense of Cystic Fibrosis Lungs

“…Given that ceramide also plays a very critical role in cystic fibrosis and normalization of ceramide levels by blockers of the acid sphingomyelinase has been shown to prevent infection and inflammation in cystic fibrosis patients [42][43][44], we hypothesize that a therapy that combines normalization of ceramide levels with inhalation of glucosylceramide and/ or sphingosine [17,37] might be the most promising way preventing or treating existing bacterial infection in CF patients in the future. Since other drugs, like antibiotics, can also be applied via an inhalation therapy in CF [45], this way of application offers the benefits of a local administration with minimal adverse systemic effects.…”

Myriocin treatment of CF lung infection and inflammation: complex analyses for enigmatic lipids

“…Recent findings highlight the role of ceramide among sphingolipids in the pulmonary demise typical of chronic obstructive pulmonary disease (COPD) and Cystic Fibrosis (CF) (Grassme 2013, Petrache 2013. Gulbins and coworkers demonstrated that ceramide accumulates in CF airways and that amytriptiline, an inhibitor of the ceramidereleasing enzyme acid sphingomyelinase, reduces lung inflammation and bacterial infection in mice and in patients (Teichgraber 2008, Riethmuller 2009). We recently demonstrated that de novo ceramide synthesis also sustains lung inflammation and infection in CF (Caretti 2014) by using a murine CF model and pulmonary Pseudomonas aeruginosa infection to measure and pharmacologically target ceramide synthesis.…”